Metabolic acidosis is a modifiable risk factor for chronic kidney disease (CKD) progression. It develops in advanced CKD due to impaired excretion of the daily load of nonvolatile acid that is generated from metabolism of dietary nutrients. Subclinical acidosis develops prior to overt acidosis and may also adversely affect clinical outcomes. Treatment of both overt and subclinical acidosis with alkali supplements slows renal disease progression in clinical trials, but use of alkali supplements may be associated with unacceptable risks in some CKD patients. Lowering nonvolatile acid load through dietary manipulation may be a complementary strategy to mitigate acidosis and improve outcomes earlier in CKD when subclinical, but not overt, acidosis is present. Using intensive patient-oriented research, we will perform detailed, direct measures of dietary intake, renal acid excretion, glomerular filtration rate and subclinical acidosis in participants with early stage 3 CKD with and without diabetes, and in healthy controls, to determine independent risk factors for subclinical acidosis. Using this rich source of data, we will also validate estimates of nonvolatile acid load against gold- standard measures for future research applications. Finally, we will directly measure nonvolatile acid load in 1000 participants from the Chronic Renal Insufficiency Cohort (CRIC) study, a diverse CKD cohort, and examine its association with hard clinical outcomes over long term follow-up. We anticipate that these research aims will establish nonvolatile acid load as a modifiable risk factor in CKD that may exert adverse effects by directly contributing to subclinical acidosis, which, by definition, escapes detection in the vast majority of patients with CKD. In addition, this research will provide a rich training experience fr the PI, Dr. Julia Scialla, in physiologic and epidemiologic research. Dr. Scialla has prior trainin in clinical nephrology and epidemiology at Johns Hopkins University and a record of publication in this field which formed the basis of her research hypotheses. She will be mentored by Dr. Myles Wolf, an experienced, well-funded clinician-scientist with a broad range of skills in patient oriented research, including physiologic and epidemiologic studies. The PI will also benefit from additional advising by experts in renal epidemiology, nutrition and translational research. This Mentored Patient-Oriented Research Career Development Award will help Dr. Scialla achieve her immediate and long term goals by supporting: (1) new training in physiologic research; (2) advanced training in epidemiology; (3) the development of scientific expertise in early abnormalities of acid-base homeostasis; and (4) the generation of critical preliminary data and scientific collaborations to facilitate her transition to research independence. PUBLIC HEALTH RELEVANCE: This research will evaluate the role of dietary intake in early abnormalities of acid-base balance in diabetic and non-diabetic CKD, as well as its subsequent impact on clinical outcomes, including progression of kidney disease, need for dialysis, development of cardiovascular disease and mortality. This work will help justify a randomized trial of dietary modification to lower nonvolatile acid load and improve outcomes, early in CKD, prior to the development of overt acidosis.